Gender- and Grade-Dependent Activation of Androgen Receptor Signaling in Adult-Type Diffuse Gliomas: Epigenetic Insights from a Retrospective Cohort Study

<b>Background</b>: The androgen receptor (AR) is a ligand-dependent transcription factor of the nuclear steroid receptor superfamily, implicated in the pathogenesis of various solid tumors. The <i>AR</i> gene, located on chromosome Xq11-12, is accompanied by several X-linked genes that modulate <i>AR</i> expression and function, including <i>FLNA</i>, <i>UXT</i>, and members of the melanoma antigen gene (MAGE) family (<i>MAGEA1</i>, <i>MAGEA11</i>, <i>MAGEC1</i>, <i>MAGEC2</i>). While the AR has been investigated in multiple tumor types, its role in adult-type diffuse gliomas remains largely unexplored. Here, we characterized AR protein expression and the promoter methylation status of the AR and associated regulatory genes in adult-type diffuse gliomas. <b>Methods</b>: A retrospective analysis was conducted on 50 patients with adult-type diffuse gliomas, including IDH-mutant gliomas (grades 2-4) and IDH-wildtype glioblastomas (GBMs), classified according to the 2021 WHO criteria. AR nuclear expression was assessed by immunohistochemistry (IHC). Methylation-specific PCR and quantitative DNA methylation analyses were employed to evaluate promoter methylation of the AR and selected co-regulatory genes. <b>Results</b>: AR nuclear positivity correlated significantly with male sex (<i>p</i> = 0.04) and higher tumor grade, with the highest expression in IDH-wildtype GBMs (<i>p</i> = 0.04). In IDH-mutant gliomas, AR immunoreactivity was more prevalent in astrocytomas than in 1p/19q codeleted oligodendrogliomas (<i>p</i> = 0.02). AR expression was associated with unmethylated MGMT promoter status (<i>p</i> = 0.02). DNA methylation analysis revealed AR gene hypomethylation in tumors displaying nuclear AR positivity and in IDH-wildtype GBMs (Kruskal-Wallis <i>p</i> < 0.05). Additionally, methylation patterns of AR co-regulators located on the X chromosome suggest epigenetic regulation of AR signaling in gliomas. <b>Conclusions</b>: The findings reveal distinct AR pathway activation patterns in adult-type diffuse gliomas, particularly IDH-wildtype GBMs, suggesting that further exploration of antiandrogen therapies is warranted.